Project Summary: A number of inflammatory diseases result from excessive cytokine production (hypercytokinemia), with an important subset of these driven by inappropriate or excessive T-cell activation. Two examples of T-cell- mediated hypercytokinemia syndromes include Familial Hemophagocytic Lymphohistiocytosis (FHL) and bone marrow transplantation (BMT)-associated graft-versus-host disease (GVHD). In FHL, hypercytokinemia is directly responsible for organ failure and death, and yet some degree of cytokinemia is still needed for control of the triggering infections. For BMT, the toxicity of hypercytokinemia represents a major limitation for its clinical use in treating cancer. As limited options are available for treatment of T-cell-mediated hypercytokinemia, identification of new therapeutic strategies is necessary. This could be challenging in T-cell- mediated hypercytokinemia induced by allogeneic BMT therapy, where the anti-tumor and cytokine-producing effects of T cells need to be separated. Since TCR signaling blockade would likely lead to simultaneous abrogation of cytokine production and anti-tumor cytotoxicity, targeting a non-TCR signaling pathway that is involved only in T cell cytokine release may represent a novel strategy. Furthermore for FHL, targeting a pathway that does not completely block cytokine production, but rather restores it to normal protective levels is desirable. We hereby propose that the IL-33 signaling is a common mechanism that exacerbates T-cell-mediated hypercytokinemia syndromes via a non-TCR mechanism. IL-33 is an ?alarmin?, a molecule released upon tissue damage that can modulate immune responses. Our data show that ST2 signaling increases IFN? production by CD8+ T cells and that IL- 33 is required for FHL and GVHD pathogenesis. Thus, we hypothesize that IL-33 derived from damaged cells is critical for T-cell-mediated hypercytokinemia by enhancing the pathogenic IFN? T-cell response without affecting cytotoxic anti-tumor responses. In this proposal, we will define the cellular and molecular mechanisms by which IL-33 contributes to T-cell-mediated hypercytokinemia and uncover the source and inducing factors of IL-33 using 2 separate clinically relevant models of T-cell-mediated hypercytokinemia. Our studies include both the investigation of the mechanisms by which IL-33 promotes disease pathogenesis in animal models as well as correlating these findings to human patients with these diseases. Armed with this information, we will be poised to develop the best strategy for IL-33 blockade in T cell-mediated hypercytokinemia syndromes, with the potential to reduce mortality and morbidity in these devastating complications.